Short noncoding RNAs, evolutionarily conserved 20 to 30 nucleotide long (miRNAs, or miRs), represent a large family of gene expression regulators through their ability to prevent translation of specific mRNA into protein (Bartel, 2004; Thomas et al., 2010). Individual miRNAs may repress up to hundreds of transcripts (Friedman et al., 2009) and can regulate diverse processes including cell growth, metabolism, immunity, inflammation and cancer (Ambros, 2004; O'Connell et al.; Pedersen and David, 2008; Volinia et al., 2006), miRNA mutations or mis-expression exist in human cancers suggesting that miRNAs can function as tumor suppressors or oncogenes (oncomirs) (Esquela-Kerscher and Slack, 2006; Garzon et al., 2009). Thus, suppression of oncomirs or selective miRNA restoration in cancer cells has therapeutic relevance.
miR-335 was identified as being implicated in the growth and metastasis of the triple negative breast cancer (TNBC) cell line MDA-MB-231 derivative 4175 (LM2) (Tavazoie et al., 2008). Clinically, TNBC patients whose primary tumors have low miR-335 expression have a shorter median time to metastatic relapse (Tavazoie et al., 2008). Reportedly, miR-335 inhibits tumor re-initiation and is silenced through genetic and epigenetic mechanisms (Png et al., 2011). One of the targets of miR-335, miR-129, miR-129-2 and miR-93, is SOX4 a transcription factor involved in embryonic development and cell fate determination (Busslinger, 2004; Hong and Saint-Jeannet, 2005; Restivo et al., 2006), and in epithelial to mesenschymal transition (EMT) (Tiwari et al., 2013). SOX4 expression is elevated in various tumors, including lymphoma, colorectal cancer, cervical cancer, lung cancer, pancreatic cancer, and breast cancer. In many cancers, deregulated expression of this developmental factor has been correlated with increased cancer cell proliferation, cell survival, inhibition of apoptosis and the induction of EMT (Vervoort et al., 2013). Experiments in mice with conditional deletion of Sox4 in stratified epithelia showed resistance to chemical carcinogenesis leading to onset delay and tumor size reduction (Foronda et al., 2014).
B cells have been programmed for the enforced biogenesis and synchronous release of sncRNAs (Almanza et al., 2013). sncRNAs have been packaged as a cargo in extracellular vesicles (EVs) produced and released by the programmed B cells, and that thus induced EVs (iEVs) are enriched in predetermined sncRNAs, with an estimate of 3.6 copy number/EV (Almanza and Zanetti, 2015).